Pharmaceutical compositions of tizoxanide and nitazoxanide

ABSTRACT

The present invention relates to a pharmaceutical composition containing as active agent, solid particles of a compound selected from the group consisting of: 
     compound of formula I ##STR1## and mixtures thereof, said particles having a particle size smaller than 200 μm, the mean particle size of the said active solid particles being greater than 10 μm. 
     It also relates to a pharmaceutical composition which contains at least one pharmaceutically acceptable acid.

THE PRIOR ART

Nitrothiazole compound PH 5776 (2-acetolyloxy)-N-(5-nitro-2-thiazolyl)benzamide) is a compound of formula II ##STR2##

The preparation and uses of this compound are disclosed in U.S. Pat. No.3,950,351, as well as in publications made by Applicant.

In U.S. Pat. No. 3,950,351, the compound of formula II is prepared byreacting ##STR3##

This reaction is not suitable for the preparation of pure compound offormula I.

In WO 95/28393, applicant discloses a method for the manufacture of purecompound of formula I, as well as the use of the composition containinga mixture of compounds of formula I and II.

It has been shown that compound of formula I is effective againstparasites, bacteria, fungi and viruses although it does not contain anacyloxy group.

Now, it has now been observed in animal studies and in human clinicalstudies, that the efficacy of a treatment, using the compounds offormula I and II as prepared by the methods disclosed in saidpublications, is dependent upon the particle size of the active drugsubstance and the stability of the compounds.

The aim of the present invention is a pharmaceutical composition whichis consistently and optimally effective against parasites, bacteria,fungi and viruses in animals and humans.

Another aim of the present invention is a pharmaceutical compositionthat maintains its stability after six months or more of storage.

BRIEF DESCRIPTION OF THE INVENTION

The present invention relates to a pharmaceutical composition for oraladministration, as a solid dosage form, a liquid suspension, or a paste,and also to a pharmaceutical composition for topical or intravaginalapplication as a paste, ointment or cream.

The composition of the invention contains an effective amount of solidparticles having a particle size smaller than 200 μm of a compoundselected from the group consisting of: ##STR4## and mixtures thereof, inwhich the mean particle size of the said active solid particles having aparticle size smaller than 200 μm being greater than 10 μm. Hereafter inthe present specification, the wording "the said active agent" meansparticles of compound of formula I, compound of formula II and mixturesthereof, the said particles having a particle size smaller than 200 μm,the means particle size of the said active solid particles being greaterthan 10 μm.

For purposes of the present specification, the range of particle sizesof samples of compound of formula I and compound of formula II and themean particle size of samples of compound of formula I and compound offormula II shall be those determined by a COULTER® Counter LS 100. Thisequipment uses laser light at 750 nm to size particles from 0.4 to 900μm in diameter by light diffraction. The samples are measured in waterwith a small amount of Triton X-100 in order to increase the wettabilityand deflocculate the powder.

It has been observed that solid particles of compound of Formula I,compound of Formula II, or mixtures thereof having a particle sizebetween 170 and 520 μm (means particle size=352 μm) have a limitedefficacy when administered orally to animals or humans.

It has also been observed in dogs that the oral administration of asingle dose of 50 milligrams per kilogram of solid particles of compoundof Formula I and compound of Formula II having a particle size smallerthan 5 μm, caused severe adverse reactions in the animals.

It has now been discovered that in order to have a very effective andsafe treatment of infections caused by parasites, bacteria, fungi andviruses in humans and animals, the pharmaceutical composition, either asolid dosage form or an aqueous suspension must contain the effectivedose of the active agent in the form of solid particles having aparticle size smaller than 200 μm and containing compound of formula Iand/or compound of formula II, the mean particle size of the said activesolid particles being greater than 10 μm.

The composition of the invention possibly contains particles of compoundof formula I and/or compound of formula II with a size larger than 200μm. However, the presence of a high content of such particles having asize larger than 200 μm with respect to the content of particles havinga size between 5 and 200 μm significantly reduces the chemotherapeuticactivity of the composition. Preferably, the pharmaceutical compositionsof the invention do not contain more than 5% of solid particles ofcompound of formula I and/or compound of formula II having a size largerthan 200 μm. Most preferably, the pharmaceutical compositions of theinvention contain substantially no solid particles of compound offormula I and/or compound of formula II having a size larger than 200μm.

The composition possibly contains particles of compound of formula Iand/or compound of formula II with a size less than 5 μm. The presenceof a high content of particles of compound of formula I and/or compoundof formula II having a size less than 5 μm with respect to the contentof particles having a size between 5 and 200 μm can produce adverseeffects in animals or in humans. In addition, it has been observed thatparticles having a size less than 5 μm are more rapidly absorbed formthe gastro-intestinal tract into the bloodstream, and therefore are notas effective against parasites, bacteria, fungi and viruses whichcommonly live within the gastro-intestinal tract of animals and humans.Preferably, the pharmaceutical compositions of the invention do notcontain more than 10% of solid particles of compound of formula I and/orcompound of formula II having a size less than 5 μm. Most preferably,the pharmaceutical compositions of the invention contain substantiallyno solid particles of compound of formula I and/or compound of formulaII having a size less than 5 μm.

The skilled scientist could not predict that the particle size ofcompound of Formula I and compound of Formula II would have such asignificant impact upon its antimicrobial activity in animals and inhumans. For example, in studies conducted by the Inventor,anti-parasitic compounds such as albendazole, mebendazole, niclosamide,praziquantel and metronidazole have not demonstrated such a markeddifference in anti-parasitic activity in animals or humans which wasdependent upon their particle size. In addition, a skilled scientistcould not predict that particle sizes of compound of Formula I andcompound of Formula II would have such an adverse impact upon theability of animals or humans to tolerate the administration of saidactive agent.

Advantageously, the mean particle size of the said active solidparticles is between 10 and 100 μm, preferably between 20 and 50 μm.Examples of preferred compositions are:

a composition for which less than 10% of the said active solid particleshas a particle size larger than 100 μm;

a composition for which at least 50% of the said active solid particleshas a particle size smaller than 50 μm.

In accordance with a preferred embodiment of the composition, less than10% of the said active solid particles has a particle size smaller than5 μm.

Advantageously, in order to have excellent efficacy against a broadspectrum of parasites, bacteria, fungi and viruses, the distributionfactor of the said active solid particles is between 0.8 and 2,preferably between 1.1 and 1.9, most preferably greater than 1.5, saiddistribution factor being calculated by the following formula:

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90% +.O slashed..sub.10%)/2)

in which

F_(90%) is the distribution factor at 90%;

.O slashed._(90%) is the maximum particle size of the fraction ofparticles corresponding to 90% of the said active solid particles, and

.O slashed._(10%) is the maximum particle size of the fraction ofparticles corresponding to 10% of the said active solid particles.

The invention also relates to pharmaceutical compositions describedabove which contain advantageously at least one pharmaceuticallyacceptable acid. Examples of such acids are: citric acid, glutamic acid,succinic acid, ethanesulfonic acid, acetic acid, tartric acid, ascorbicacid, methanesulfonic acid, fumaric acid, adipic acid, malic acid andmixtures thereof. Citric acid is very appropriate. The presence of saidacid improves the stability of the active agent or agents.

The ratio of the weight of pharmaceutically acceptable acid/the weightof said active solid particles is advantageously between 0.01 and 0.5,preferably between 0.03 and 0.2. Advantageously, the amount of acid issufficient for adjusting the pH of the suspension between 2 and 6,preferably between 3 and 5, most preferably between 3.5 and 4.5.

The active agent or agents used in the solid dosage form or suspensionis advantageously a mixture of solid particles of compounds of formula Iand of formula II with a particle size smaller than 200 μm, the weightcontent of compound of formula II with respect to the weight ofcompounds of Formula I and of Formula II of said mixture being comprisedbetween 0.5 and 20%, preferably between 0.5 and 10%.

According to a specific embodiment of the invention, active particles ofcompound of formula I and compound of formula II are prepared by themethods described hereabove and are then milled so that less than 10% ofsaid active particles are larger than 100 μm, less than 50% of saidparticles are larger than 50 μm and less than 10% of said activeparticles are smaller than 5 μm in size, the mean particle size beingbetween 20 and 590 μm. Said active particles are then granulated using amixture containing active solid particles and at least one granulatingagent. Examples of granulating agent are: polyvinylpyrrolidone, water,alcohol, sucrose hydroxyl cellulose and mixture thereof. Advantageously,at least one pharmaceutically acceptable acid is added during thegranulation process.

The invention relates to solid dosage forms containing a composition ofthe invention such as tablets, dispersible tablets, coated tablets,matrixes, etc. The dosage form of the invention contains, for example:

solid active particles with a particle size smaller than 200 μm, lessthan 10% of said particles having a size larger than 100 μm, less than50% of said particles having a size larger than 50 μm and less than 10%of said particles having a size less than 5 μm, the means particle sizebeing between 20 and 50 μm.

at least one granulating agent;

at least one wetting agent;

at least one starch derivative, and

at least one pharmaceutically acceptable acid which is preferably addedduring the granulation process.

Liquid dosage forms such as aqueous suspensions of the inventioncontain, for example:

as active agent, solid particles containing a compound of formula Iand/or a compound of formula II having a particle size smaller than 200μm, less than 10% of said particles having a size larger than 100 μm,less than 50% of said particles having a size larger than 50 μm and lessthan 10% of said particles having a size less than 5 μm, and

at least one granulating agent;

at least one wetting agent;

at least one pharmaceutically acceptable acid, the pH of the suspensionbeing between 2 and 6, preferably between 3 and 5, most preferablybetween 3.5 and 4.5;

at least one thickener, for example a Xanthan gum, a guar gum,crystalline cellulose, carruba gum, carboxymethylcellulose or a mixturethereof.

Paste or ointment forms of the invention suitable for oraladministration contain, for example:

as active agent, solid particles containing a compound of formula Iand/or a compound of formula II having a particle size smaller than b200 μm, less than 10% of said particles having a size larger than 100μm, less than 50% of said particles having a size larger than 50 μm andless than 10% of said particles having a size less than 5 μm, and

at least one wetting agent;

at least one pharmaceutically acceptable acid, the pH of the suspensionbeing between 2 and 6, preferably between 3 and 5, most preferablybetween 3.5 and 4.5;

at least one thickener, for example a Xanthan gum, a guar gum,crystalline cellulose, carruba gum, carboxymethylcellulose or a mixturethereof.

Paste or ointment forms for topical or intravaginal application contain,for example:

as active agent, solid particles containing a compound of formula Iand/or a compound of formula II having a particle size smaller than 200μm, less than 10% of said particles having a size larger than 100 μm,less than 50% of said particles having a size larger than 50 μm and lessthan 10% of said particles having a size less than 5 μm, and

at least one wetting agent;

at least one pharmaceutically acceptable acid, the pH of the suspensionbeing between 2 and 6, preferably between 3 and 5, most preferablybetween 3.5 and 4.5;

cetylic alcohol and/or glyceride derivatives and/or propyleneglycol;

at least one thickener, for example a Xanthan gum, a guar gum,crystalline cellulose, carruba gum, carboxymethylcellulose or a mixturethereof.

Such pharmaceutical compositions, either as solid or liquid dosage formsor as pastes or ointments, can possible contain additional active agentssuch an antibiotics, anti-viral agents or proton pump inhibitors. Whileit is not advantageous, it is also possible that such pharmaceuticalformulations may contain solid particles of compound of Formula I and/orcompound of Formula II which are larger than 200 μm.

The pharmaceutical compositions described are suitable for treatinghuman and animal infections caused by parasites, bacteria, fungi andviruses.

BRIEF DESCRIPTION OF THE DRAWING

FIG. 1 shows the percentage of active particles having a size smallerthan .O slashed.μm.

DESCRIPTION OF EXAMPLES OF PHARMACEUTICAL COMPOSITIONS

Dry pure compound of formula I (desacetyl-nitazoxanide) and dry purecompound of formula II (Nitazoxanide) were submitted to a grinding andsized by means of a mesh screen.

After grinding, the particles of compound of formula I, of formula IIand mixtures thereof had the particle size distribution as given inFIG. 1. Said FIG. 1 shows the percentage of particles having a sizesmaller than .O slashed.μm.

From said figure, it appears that:

less than 10% of the particles had a particle size smaller thanapproximately 5 μm;

less than 10% of the particles had a particle size larger thanapproximately 70 μm;

the mean particle size is approximately 40 μm;

the distribution factor of the particles is about 1.73, saiddistribution factor being calculated by the following formula:

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90 %+.O slashed..sub.10%)/2)

in which

F_(90%) is the distribution factor at 80%;

.O slashed._(90%) is the maximum particle size of the fraction ofparticles corresponding to 90% of the said active solid particles, and

.O slashed._(10%) is the maximum particle size of the fraction ofparticles corresponding to 10% of the said active solid particles.

Specific examples of such compositions are disclosed in the followingTables.

                  TABLE A                                                         ______________________________________                                        Example of composition of dispersible tablets for oral                        administration containing compound of Formula II and                          compound of Formula I as active agents.                                       ______________________________________                                        Nitazoxanide (99%) + desacetyl-nitazoxanide (1%)                                                         200 mg                                             Microcrystalline cellulose 116 mg                                             Avicel pH 102 sold by FMC-USA                                                 Crospovidone               25 mg                                              Magnesium stearate         3 mg                                               Colloidal silicon dioxide  5 mg                                               Citric acid                10 mg                                              Strawberry flavor No. 877720 sold by Robertet                                                            10 mg                                              Sodium saccharinate        2 mg                                               ______________________________________                                    

                  TABLE B                                                         ______________________________________                                        Example of composition of coated tablets for oral administration              containing compound of Formula II and compound of Formula I                   as active agents.                                                             ______________________________________                                        Nitazoxanide               500 mg                                             Maize starch               60 mg                                              Pregelatinized Maize starch                                                                              70 mg                                              Hydroxypropyl methylcellulose                                                                            5 mg                                               Sucrose                    20 mg                                              Sodium starch glycollate   30 mg                                              Citric acid                25 mg                                              Talc                       8 mg                                               Magnesium stearate         7 mg                                               ______________________________________                                         Coatings:                                                                     Hot sugar solution or a film coating being sprayed on the tablets or          granules containing 500 mg active agent.                                 

                  TABLE C                                                         ______________________________________                                        Example of an aqueous suspension for oral administration                      containing compound of Formula II and compound of Formula I                   as active agents. The pH of the suspension was about 4.1.                     ______________________________________                                        Nitazoxanide (98%) + desacetyl-Nitazoxanide (2%)                                                           2 g                                              Distilled water              100 ml                                           Sodium benzoate              0.2 g                                            Saccharose                   30.5 g                                           Xanthan gum                  0.2 g                                            Microcrystalline cellulose and carboxymethylcellulose sodium                                               0.8 g                                            Avicel RC-591 sold by FMC - USA                                               Citric acid                  0.2 g                                            Dihydrated sodium citrate    50 mg                                            Strawberry flavor No. 877720 sold by Robertet                                                              125 mg                                           Red dye No. 33 D and C       1 mg                                             ______________________________________                                    

                  TABLE D                                                         ______________________________________                                        Example of a paste for oral administration containing compound                of Formula II and compound of Formula I as active agents.                     ______________________________________                                        Nitazoxanide (98%) + desacetyl-Nitazoxanide (2%)                                                           500 mg                                           Mineral oil                  10 g                                             Brown sugar                  1 g                                              Microcrystalline cellulose and carboxymethycellulose sodium                                                0.8 g                                            Avicel RC-591 sold by FMC                                                     Citric acid                  0.2 g                                            ______________________________________                                    

                  TABLE E                                                         ______________________________________                                        Example of a paste or ointment formulation for intravaginal or                topical application, said paste or ointment containing compound               of Formula II and compound of Formula I as active agents.                     ______________________________________                                        Nitazoxanide (98%) + desacetyl-Nitazoxanide (2%)                                                          8 g                                               Cremaphor A6                2 g                                               Cremaphor A25               1.5 g                                             Mineral oil                 7 g                                               Luvitol EHO                 7 g                                               Glycerol monoester          4 g                                               Cetylic alcohol             3 g                                               Simeticone                  0.5 g                                             Germaben II                 1 g                                               Propyleneglycol             3.5 g                                             Distilled water             62.5 g                                            ______________________________________                                    

The pharmaceutical compositions of the invention are compositions havinga broad spectrum of action on parasites, bacteria, fungi and viruses,especially when administered orally.

The compositions can contain excipients known as such for the purpose ofpreparing forms suitable for oral administration.

The compositions contain advantageously a wetting agent and possibly astarch derivative such as those disclosed in U.S. Pat. No. 5,578,621,the content of which is incorporated herein by reference for disclosingpossible wetting agents and starch derivatives. The wetting agent asdescribed in U.S. Pat. No. 5,578,621 serves as a dispersing agent.

The efficacy and the safety of the pharmaceutical compositions disclosedhereabove were excellent in animals and in humans. Specifically, inhuman clinical studies, it has been observed that the efficacy of thepharmaceutical compositions described hereabove are significantly moreeffective in treating parasitic infections than the same formulationsusing active compound having particle sizes between 170 and 520 μm (meanparticle size=352 μm), even when the larger sized particles wereadministered to patients at doses up to three times higher and forlonger periods of time. Examples of cure rates obtained are shown belowin Table D.

                                      TABLE F                                     __________________________________________________________________________    Comparison of results of human clinical studies using                         compounds of Formula I and Formula II having particle                         sizes ranging from 170 μm to 520 μm (mean = 352 μm)                  with results obtained using Formula I and Formula II                          having particle sizes ranging from 5 μm to 200 μm (mean =               34 μm).                                                                              Compound of Formula I (98%) + Compound of                                     Formula II (2%)                                                               Particle sizes 170 to 520 μm                                                               Particle sizes 5 to 200 μm                                 Dose = 15 to 50 mg/kg/day for 3 to 7                                                          Dose = 15 mg/kg/day for                                       days            days                                                Parasite  No. Cured/Total = % Cure Rate                                                                 No. Cured/Total = % Cure Rate                       __________________________________________________________________________    Blastocystis hominis                                                                    12/27 = 44%     10/10 = 100%                                        Entamoeba histolytica                                                                   29/47 = 62%     106/133 = 80%                                       Giardia lamblia                                                                         11/37 = 30%     50/73 = 68%                                         Ascaris lumbricoides                                                                    3/69 = 4%       144/179 = 80%                                       Trichuris trichiura                                                                     7/48 = 15%      58/79 = 73%                                         __________________________________________________________________________

For each of the parasites listed in Table F, the proportional cure rateswere significantly better for the patients treated with active particlesbetween 5 and 200 μm than for those treated with active particlesranging from 170 μm to 520 μm in size, with a statistical significancein each case being p<0.02 (using a standard X² test). This was the caseeven through the doses of the larger particle size active agent wereusually higher and the duration of treatment was often longer than thatadministered to the patients receiving pharmaceutical compositions ofactive agent having particle sizes smaller than 200 μm. There were noserious adverse effects reported for either group of patients.

Results similar to those described above for human studies have alsobeen observed in animal testing.

In addition, the adverse reactions observed in dogs after oraladministration of a single dose of 50 milligrams per kilogram ofcompound of Formula I and compound of Formula II have not been observedin extensive studies in animals using compound of Formula I and compoundof Formula II have a particle size between 5 and 200 μm (mean>10 μm),even when the same dose or a higher dose of the compounds wereadministered daily for 90 days or longer.

Moreover, said compositions were stable (even when subjected totemperatures of 40° C. and 65% relative humidity for six months or, inthe case of liquid suspensions, when suspended in water under theseconditions for 3 months) thereby assuring that the active ingredients donot degrade and that the compositions maintain their efficacy for aperiod of time after their preparation which is suitable for medicinaland commercial purposes.

It is obvious that the composition of the invention may contain furtheractive agents, for example in the form of solid particles.

What I claim is:
 1. A pharmaceutical composition for oral administrationcontaining as active agent, an effective amount of solid particleshaving a particle size smaller than 200 μm of a compound of formula II##STR5## in which the mean particle size of the said active solidparticles is greater than 10 μm.
 2. The composition of claim 1, in whichthe mean particle size of the said active solid particles is between 10and 100 μm.
 3. The composition of claim 1, in which the mean particlesize of the said active solid particles is between 20 and 50 μm.
 4. Thecomposition of claim 1, in which less than 10% of the said active solidparticles has a particle size larger than 100 μm.
 5. The composition ofclaim 1, in which at least 50% of the said active solid particles has aparticle size smaller than 50 μm.
 6. The composition of claim 1, inwhich less than 10% of the said active solid particles has a particlesize smaller than 5 μm.
 7. The composition of claim 1 in which thedistribution factor of the said active solid particles is between 0.8and 2, said distribution factor being calculated by the followingformula:

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90% +.O slashed..sub.10%)/2)

in which F_(90%) is the distribution factor at 90%; .O slashed._(90%) isthe maximum particle size of the fraction of particles corresponding to90% of the said active solid particles, and .O slashed._(10%) is themaximum particle size of the fraction of particles corresponding to 10%of the said active solid particles.
 8. The composition of claim 1, inwhich the distribution factor of the said active solid particles isbetween 1.1 and 1.9, said distribution factor being calculated by thefollowing formula

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90% +.O slashed..sub.10 %)/2)

in which F_(90%) is the distribution factor at 90% .O slashed._(90%) isthe maximum particle size of the fraction of particles corresponding to90% of the said active solid particles, and .O slashed._(10%) is themaximum particle size of the fraction of particles corresponding to 10%of the said active solid particles.
 9. The composition of claim 1, whichcomprises at least one pharmaceutically acceptable acid.
 10. Thecomposition of claim 1, which comprises at least one pharmaceuticallyacceptable acid selected from the group consisting of citric acid,glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartricacid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid,malic acid and mixtures thereof.
 11. The composition of claim 10, inwhich the ratio of the weight of pharmaceutically acceptable acid/theweight of said active solid particles is between 0.01 and 0.5
 12. Thecomposition of claim 10, in which the ratio of the weight ofpharmaceutically acceptable acid/the weight of said active solidparticles is between 0.03 and 0.2.
 13. A pharmaceutical composition fororal administration containing:as active agent, an effective amount ofsolid particles having a particle size smaller than 200 μm of a compoundof formula II ##STR6## in which the mean particle size of the saidactive solid particles is greater than 10 μm; and at least onegranulating agent.
 14. The composition of claim 13, in which the meanparticle size of the said active solid particles is comprised between 10and 100 μm.
 15. The composition of claim 13, in which the mean particlesize of the said active solid particles is comprised between 20 and50μm.
 16. The composition of claim 13, in which less than 10% of thesaid active solid particles has a particle size larger than 100 μm. 17.The composition of claim 13, in which at least 50% of the said activesolid particles has a particle size smaller than 50 μm.
 18. Thecomposition of claim 13, in which less than 10% of the said active solidparticles has a particle size smaller than 5 μm.
 19. The composition ofclaim 13, in which the granulated active solid particles contains from 2to 99.97% by weight of the said active compound and from 0.03 to 10% byweight of a granulating agent.
 20. The composition of claim 19, in whichthe granulating agent is selected from the group consisting ofpolyvinylpyrrolidone, water, alcohol, sucrose hydroxyl cellulose andmixture thereof.
 21. The composition of claim 13, in which thegranulated active solid particles contain at least one pharmaceuticallyacceptable acid.
 22. The composition of claim 13, in which thegranulated active solid particles contain at least one pharmaceuticallyacceptable acid selected from the group consisting of citric acid,glutamic acid, succinic acid, ethanesulfonic acid, acetic acid, tartricacid, ascorbic acid, methanesulfonic acid, fumaric acid, adipic acid,malic acid and mixtures thereof.
 23. The composition of claim 22, inwhich, for the granulated active solid particles, the ratio of theweight of pharmaceutically acceptable acid/the weight of said activeagent is between 0.01 and 0.5.
 24. A solid dosage form for oraladministration containing:as active agent, an effective amount of solidparticles having a particle size smaller than 200 μm of a compound offormula II ##STR7## in which the mean particle size of the said activesolid particles is greater than 10 μm; at least one wetting agent, andat least one starch derivative.
 25. The dosage form of claim 24, inwhich the mean particle size of the said active solid particles isbetween 10 and 100 μm.
 26. The dosage form of claim 24, in which themean particle size of the said active solid particles is between 20 and50 μm.
 27. The dosage form of claim 24, in which less than 10% of thesaid active solid particles has a particle size larger than 100 μm. 28.The dosage form of claim 24, in which at least 50% of the said activesolid particles has a particle size smaller than 50 μm.
 29. The dosageform of claim 24, in which less than 10% of the said active solidparticles has a particle size smaller than 5 μm.
 30. The composition ofclaim 24, in which the distribution factor of the said active solidparticles is between 0.8 and 2, said distribution factor begincalculated by the following formula:

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90% +.O slashed..sub.10%)/2)

in which F_(90%) is the distribution factor at 90%; .O slashed._(90%) isthe maximum particle size of the fraction of particles corresponding to90% of the said active solid particles, and .O slashed._(10%) is themaximum particle size of the fraction of particles corresponding to 10%of the said active solid particles.
 31. The composition of claim 24, inwhich the distribution factor of the said active solid particles isbetween 1.1 and 1.9, said distribution factor being calculated by thefollowing formula

    F.sub.90% =(.O slashed..sub.90% -.O slashed..sub.10%)/((.O slashed..sub.90% +.O slashed..sub.10%)/2)

in which F_(90%) is the distribution factor at 90%; .O slashed._(90%) isthe maximum particle size of the fraction of particles corresponding to90% of the said active solid particles, and .O slashed._(10%) is themaximum particle size of the fraction of particles corresponding to 10%of the said active solid particles.
 32. The dosage form of claim 24,which includes particles of at least one pharmaceutically acceptableacid.
 33. The dosage form of claim 24, in which the active particles aregranulated, said granulated active agent containing form 2 to 99.97% byweight of the said active compound and from 0.03 to 10% by weight of agranulating agent.
 34. The dosage form of claim 33, in which thegranulating agent is selected from the group consisting ofpolyvinylpyrrolidone, water, alcohol, sucrose hydroxyl cellulose andmixture thereof.
 35. The dosage form of claim 24, said form comprisedof:solid granulated active particles, said granulated active particlescontaining from 2 to 90% by weigh of the said active compound, from 0.03to 10% by weight of a granulating agent, and at least onepharmaceutically acceptable acid; at least one wetting agent; at leastone starch derivative, and at least one pharmaceutically acceptableacid.
 36. An aqueous or other liquid suspension of solid particles fororal administration, said suspension containing:as active agent, aneffective amount of solid particles having a particle size smaller than200 μm of a compound of formula II ##STR8## in which the mean particlesize of the said active solid particles is greater than 10 μm; and atleast one pharmaceutically acceptable acid, the pH of the suspensionbeing between 2 and
 6. 37. The suspension of claim 36, in which the pHof the suspension is between 3 and
 5. 38. An aqueous or other liquidsuspension of solid particles for oral administration, said suspensioncontaining:as active agent, an effective amount of solid particleshaving a particle size smaller than 200 μm of a compound of formula II##STR9## in which the mean particle size of the said active solidparticles is greater than 10 μm; a granulating agent; and at least onepharmaceutically acceptable acid, the pH of the suspension being between2 and
 6. 39. The suspension of claim 38, in which the pH of thesuspension is between 3 and
 5. 40. A pharmaceutical composition for oraladministration containing:as active agent, an effective amount of solidparticles having a particle size smaller than 200 μm of a compound offormula II ##STR10## in which the mean particle size of the said activesolid particles is greater than 10 μm; at least one pharmaceuticallyacceptable acid.
 41. A paste for oral administration containing:asactive agent, an effective amount of solid particles having a particlesize smaller than 200 μm of a compound of formula II ##STR11## in whichthe mean particle size of the said active solid particles is greaterthan 10 μm; at least one wetting agent; at least one pharmaceuticallyacceptable acid, the pH of the paste being between 2 and 6; at least onethickener.
 42. The paste of claim 41, in which the thickener is selectedfrom the group consisting of Xanthan gum, a guar gum, crystallinecellulose, carruba gum, carboxymethylcellulose or a mixture thereof. 43.A paste for topical administration containing:as active agent, aneffective amount of solid particles having a particle size smaller than200 μm of a compound of formula II ##STR12## in which the mean particlesize of the said active solid particles is greater than 10 μm; at leastone wetting agent; at least one additive selected from the groupconsisting of cetylic alcohol, glyceride derivatives, propyleneglycoland mixtures thereof; at least one thickener.
 44. A paste forintravaginal administration containing:as active agent, solid particleshaving a particle size smaller than 200 μm of a compound of formula II##STR13## in which the mean particle size of the said active solidparticles is greater than 10 μm; at least one wetting agent; at leastone additive selected from the group consisting of cetylic alcohol,glyceride derivatives, propyleneglycol and mixtures thereof; at leastone thickener.